Dr. Simon Best is a junior faculty member in the Department of Otolaryngology ? Head and Neck Surgery at the Johns Hopkins School of Medicine where his clinical practice is dedicated to voice and airway disorders. With the support of this Mentored Career Development Award, Dr. Best seeks to better understand the immunologic environment that allows Human Papillomavirus types 6 and 11 to elude the immune system and cause Recurrent Respiratory Papillomatosis (RRP). Dr. Best will enhance his research knowledge and skills with coursework in immunology, biostatistics, and clinical trial design, and receive directed mentorship by an interdisciplinary team of experienced researchers. He will be immersed in the interdisciplinary research environment of the Cervical Cancer SPORE program at Johns Hopkins, which is a unique center of researchers dedicated to HPV-associated diseases. This award will provide Dr. Best with the resources that he needs to become an independent investigator and future leader in the treatment of papillomatosis. In Aim 1, Dr. Best will build on his prior research experience in papillomatosis to test the hypothesis that PD-1 and PD-L1 play a role in the immunologic microenvironment in a population of RRP patients and determine if expression of these markers is correlated with clinical disease severity. He will also seek to understand the mechanisms that drive PD-L1 expression in papilloma and the functional consequences of this pathway in RRP. In Aim 2, he will study a mouse model of papilloma to further understand how papilloma develops in immunocompetent mice, and test if DNA vaccines are able to treat this infection. He will further determine if blockade of the PD-1 pathway enhances the activity of DNA vaccination in this murine model of papilloma. Upon successful completion of this project, there will be promising data to suggest a role for immunologic therapies in RRP, and a better understanding of the immunologic factors that allow laryngeal papillomas to grow and evade immune-mediated clearance. Identifying these factors could lead directly to the testing of novel therapeutics in papillomatosis, as well as suggest generalized mechanisms for how the HPV virus escapes the immune system. At the conclusion of this award, Dr. Best will have obtained the preliminary data needed to successfully compete for independent funding and achieve long-term success as a surgeon-scientist dedicated to this debilitating disease.